1. Field of the Invention
The present invention relates to a process for synthesizing an anhydroecgonine derivative that is an intermediate for synthesis of an alkaloid having the same tropane skeleton as that of cocaine having an affinity for dopamine transporters pharmacologically, and a process for synthesizing a phenyltropane derivative by using said anhydroecgonine derivative as an intermediate for the synthesis.
2. Related Art
Cocaine is an alkaloid contained in the leaves of, for example, coca (Erythroxylon coca) growing in the Andes in South America. A pure preparation of this alkaloid was isolated for the first time by Niemann et al. in 1860. Cocaine tastes bitter and its special effects such as numbness of tongue and sensory paralysis have been revealed. Freud and Koller applied cocaine to clinical use for the first time. In 1884, Freud extensively investigated the physiological effects of cocaine. On the other hand, Koller applied cocaine to a local anesthetic in the ophthalmic operation. Thereafter, local anesthesia using cocaine has rapidly come to be employed in various fields of medicine. Einhorn investigated the synthesis of a substitute for cocaine (Goodman, xe2x80x9cYakurishoxe2x80x9d, 8th ed., Hirokawa Shoten Ltd.). Since cocaine has recently been found to have an affinity for dopamine transporters, it has been shown that cocaine derivatives are useful as tracer ligands, in particular, radioactive tracers for imaging agents in nuclear medicine.
Cocaine blocks the uptake of dopamine into nerve cells because of its affinity for dopamine transporters that are membrane proteins capable of reuptake of dopamine released into synaptic clefts from dopamine nerve ending. In recent years, this mechanism of action of cocaine has been noticed in the field of nuclear medicine and attempts have been made to give a diagnosis by imaging of the dopamine transporters. Accordingly, radiolabeled products of various cocaine analogs were investigated. Neumeyer et al. found compounds such as 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)-tropane which are neuroprobes useful as radioactive tracers having an affinity for the dopamine transporters for use in single-photon emission computed tomography (SPECT) or positron emission tomography (PET) in nuclear medicine. It has been shown that the brain uptake and clearance from brain of these compounds are slower than those of cocaine itself, and that the uptake of the compounds into striatum substantially reflects the distribution of dopamine reuptake site (U.S. Pat. No. 5,310,912). In addition, Neumeyer et al. investigated various phenyltropane derivatives and consequently confirmed that N-(3-fluoropropyl)-2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)nortropane is a compound further improved, for example, in pharmacokinetic problems such as residence time as compared with 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)tropane. It has been reported that the estimation of the change of dopamine nerve cells by imaging of striatum dopamine transporters with the radioiodinated (Iodine-123) phenyltropane derivatives gives useful information for early diagnosis of Parkinson""s disease and judgment on the seriousness of this disease (Booiji et al., Eur. J. Nucl. Med., 1997, 24, 68-71).
At present, as shown in the scheme A exhibited hereinafter, the tropane skeleton as basic skeleton of cocaine is obtained as anhydroecgonine methyl ester by hydrolyzing cocaine as a starting material into ecgonine, dehydrating the ecgonine, and converting the dehydrated product to methyl ester (Kozikowski et al., J. Am. Chem. Soc., 1995, 38, 3086). From this anhydroecgonine methyl ester, there can easily be synthesized a derivative having an optically active tropane skeleton having the same absolute configuration as that of natural (xe2x88x92)-cocaine, such as 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)tropane or N-(3-fluoropropyl)-2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)-nortropane. Cocaine, however, is designated as a narcotic because of problems such as drug dependence. For that reason, there are various difficulties in obtaining and handling cocaine. Therefore, there is desired the development of a process for synthesizing a compound analogous to cocaine which does not cause the difficulties.
Since early times, attempts have been made to synthesize a cocaine analogous (a tropane derivative) without using cocaine as a starting material. Robinson et al. synthesized tropinone by condensing a dialdehyde, methylamine and acetonedicarboxylic acid ethyl ester (Robinson et al., J. Chem. Soc., 1917, 762-768; Findlay et al., J. org. Chem., 1957, 22, 1385-1394). Neumeyer investigated the synthesis of 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)tropane using tropinone as a starting material (Neumeyer et al., J. Med. Chem., 1993, 36, 1914-1917). Tufariello et al. attempted stereoselective synthesis of cocaine (Tufariello et al., Tetrahedron Lett., 1978, 20, 1733-1736). However, in each of these synthetic processes, the synthesis should be carried out by producing cocaine or ecgonine methyl ester as an intermediate in the synthetic procedure. Carrying out the synthesis by replacing the substituent on the nitrogen atom with another substituent can be thought of but is disadvantageous in that it requires several additional steps. Grundmann et al. synthesized dl-ecgonidine and its ester from a cycloheptatrienecarboxylic acid derivative synthesized from benzene and a diazoacetic acid derivative, without producing an ecgonine derivative as an intermediate (Grundmann et al., Justus Liebigs Ann. Chem., 1957, 605, 24-32, and U.S. Pat. No. 2,783,235). However, no starting material other than the cycloheptatrienecarboxylic acid derivative is described in these references. 
Since almost all of the above processes for synthesizing a tropane derivative are processes for synthesizing a racemic cocaine derivative, an optical resolution step is required for obtaining an optically active tropane derivative having the same absolute configuration as that of (xe2x88x92)-cocaine. For example, in order to obtain starting material for synthesizing various tropane derivatives, Grundmann et al. attempted the optical resolution of dl-ecgonidine ethyl ester by recrystallization and Wang et al. attempted the optical resolution of dl-carbomethoxytropinone by recrystallization. However, it is generally difficult to obtain a compound (1-form, (xe2x88x92)-form) having an extremely high optical purity, only by optical resolution by recrystallization. Selective synthesis of optically active anhydroecgonine methyl ester by an asymmetric synthetic method was also carried out by Davies et al. (J. Org. Chem., 1991, 56, 5696-5700, and Japanese Patent Application Kohyo No. 7-504665) and Node et al. (Tetrahedron Lett., 1999, 40, 5357-5360). However, neither of their synthetic processes can give a desired compound having a satisfactory optical purity, for example, because the processes comprise a large number of steps for the synthesis.
In view of such situation, the present invention is intended to provide a process for synthesizing an anhydroecgonine derivative useful as an intermediate for synthesis of a tropane derivative, without using cocaine as a starting material, and a process for synthesizing a tropane derivative by using said anhydroecgonine derivative as an intermediate for the synthesis.
One aspect of the present invention is directed to a process for synthesizing an anhydroecgonine derivative which comprises reacting a cycloheptatriene derivative of the formula (1) shown below with a primary amine, a salt thereof or ammonia.
That is, it is directed to a process for synthesizing an anhydroecgonine derivative which comprises reacting a cycloheptatriene derivative represented by the formula (1): 
wherein n is an integer of 0 or 1; and R1 is a cyano group in the case of n being 0, and R1 is selected from an alkyl group and an aralkyl group in the case of n being 1, with a primary amine represented by the formula (2):
R2NH2xe2x80x83xe2x80x83(2)
wherein R2 is a hydrogen atom, an unsubstituted alkyl group, a substituted alkyl group, an unsubstituted aralkyl group or a substituted aralkyl group, or a salt thereof or ammonia in the presence of a base to obtain an anhydroecgonine derivative represented by the formula (3): 
wherein R1 and R2 are as defined above.
Another aspect of the present invention is directed to a process for synthesizing a phenyltropane derivative represented by the formula (4): 
wherein R3 is a group selected from the group consisting of an unsubstituted alkyl group, a substituted alkyl group, an unsubstituted aralkyl group, a substituted aralkyl group and a chelating group capable of forming a complex together with a radioactive transition metal; R4 is a group selected from the group consisting of an alkyl ester group and a chelating group capable of forming a complex together with a radioactive transition metal; L is a methylene chain of 1 to 4 carbon atoms as a connecting portion; nxe2x80x2 and nxe2x80x3 are independently an integer of 1 or 0; and X is a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom or its radioisotope, which process uses as an intermediate for the synthesis an anhydroecgonine derivative of the formula (3) obtained by reacting the above-mentioned cycloheptatriene derivative with a primary amine, a salt thereof or ammonia.
The present invention has made it possible to provide a process for synthesizing an anhydroecgonine derivative useful as an intermediate for synthesis of a tropane derivative, without using cocaine as a starting material, and a process for synthesizing a tropane derivative by using said anhydroecgonine derivative as an intermediate for the synthesis. Consequently, as compared with conventional processes for synthesizing a phenyltropane derivative, the present invention makes it possible to obtain efficiently a physiologically active phenyltropane derivative by synthesizing a phenyltropane derivative by a shortened synthetic procedure without using cocaine, ecgonine or the like as an intermediate, and carrying out optical resolution by HPLC in combination with the synthesis. For example, it has become possible to obtain an optically active phenyltropane derivative such as methyl [1R-(2-exo,3-exo)]-3-(4-iodophenyl)-8-methyl-8-azabicyclo-[3.2.1]octane-2-carboxylate, methyl [1R-(2-exo,3-exo)]-8-(3-fluoropropyl)-3-(4-iodophenyl)-8-azabicyclo-[3.2.1]octane-2-carboxylate, [1R-(2-exo,3-exo)]-2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-sulfanilethyl)amino]ethyl]amino]-ethanethiol salt or the like by a shortened synthetic procedure by using a cycloheptatriene derivativer as a starting material, using as an intermediate an anhydroecgonine derivative having a desirable substituent suitable for purposes introduced thereinto at the N-8 position, and carrying out optical resolution in a proper stage of the synthesis of the phenyltropane derivative. These compounds thus obtained have the same tropane skeleton as that of a cocaine derivative and are effectively used as a radioactive tracer for mapping of brain dopamine transporters by SPECT or PET imaging in nuclear medicine.
The anhydroecgonine derivative obtainable by the synthetic process of the present invention is synthesized without using cocaine as a starting material, and it is useful as an intermediate for synthesis of cocaine analogous which has the same tropane skeleton as that of cocaine, i.e., the basic ring structure of cocaine and has the same optical activity as in the case of deriving the analogous compound from natural (xe2x88x92)-cocaine. 
The anhydroecgonine derivative obtainable by the synthetic process of the present invention can be synthesized by the process shown in the above reaction scheme B. The cycloheptatriene derivative 1 has four isomers xcex1, xcex2, xcex3 and xcex4 relative to the position of the substituent, and any of them may be used. Cycloheptatrienecarbonitrile of the above formula 1 wherein n is 0 and R1 is a cyano group in the substituent is a preferable cycloheptatriene derivative. Cycloheptatrienecarbonitrile can be obtained by a well-known process. For example, 2,4,6-cycloheptatriene-1-carbonitrile, an isomer of cycloheptatrienecarbonitrile, can be obtained as an orange oil by dissolving tropylidene in carbon tetrachloride, brominating tropylidene by dropwise addition of bromine to obtain cycloheptatrienilium bromide, and the resulting compound was allowed to react with an aqueous potassium cyanide solution with heating (Doeling, W. von E., et al., J. Am. Chem. Soc., 79, 352-356(1957)). The primary amine, ammonia or the like, which is allowed to react with the above-mentioned cycloheptatriene derivative, is also a well-known compound synthesized by a per se well-known process.
In the above reaction scheme B, either the primary amine 2 or a salt thereof may be used. The substituent R2 of the primary amine is selected from the group consisting of a hydrogen atom, an unsubstituted alkyl group, a substituted alkyl group, an unsubstituted aralkyl group, a substituted aralkyl group, etc. Specific examples of the unsubstituted alkyl group are alkyl groups of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, etc. The substituted alkyl group includes monofluoro-substituted alkyl groups. Specific examples thereof are monofluoroethyl group, monofluoropropyl group, etc. The unsubstituted aralkyl group includes, for example, aralkyl groups of 7 to 10 carbon atoms, such as benzyl, phenethyl, phenylpropyl, phenylbutyl, etc. The substituted aralkyl group includes fluorobenzyl group, methylbenzyl group, etc.
As the anhydroecgonine derivative 3, various derivatives can be synthesized by properly selecting the substituent of the cycloheptatriene derivative 1 and the substituent R2 of the primary amine 2. In the formula 3, R1 is a cyano group in the case of n being 0, and R1 is selected from an alkyl group and an aralkyl group in the case of n being 1. Specific examples of the alkyl groups are alkyl groups of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, etc. The aralkyl groups include aralkyl groups of 7 to 10 carbon atoms, such as benzyl, phenethyl, phenylpropyl, phenylbutyl, etc.
A base such as sodium hydroxide, potassium hydroxide or the like is used in the reaction of the cycloheptatriene derivative with the primary amine or ammonia. The primary amine or ammonium may be used in itself as the base. When a salt of the primary amine is reacted, sodium hydroxide or potassium hydroxide is used as required. The reaction is carried out in a solvent such as water, methanol, ethanol, dioxane or the like at a reaction temperature of 80 to 150xc2x0 C. The anhydroecgonine derivative 3 thus obtained can be used as an intermediate in a modified process for synthesizing 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)tropane (methyl [1R-(2-exo,3-exo)]-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate), N-(3-fluoropropyl)-2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)-nortropane (methyl [1R-(2-exo,3-exo)]-8-(3-fluoropropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate) or the like, which is useful as a radioactive tracer for use in SPECT or PET for mapping dopamine transporters in brain, without producing cocaine as an intermediate.
The reaction scheme C shown below is an example of reaction scheme for synthesizing an anhydroecgonine derivative (the formula 3) and a phenyltropane derivative (the formula 6) without producing cocaine as an intermediate. In detail, the reaction scheme C is a scheme in which methyl (1RS)-8-methyl-8-azabicyclo-[3.2.1]oct-2-ene-2-carboxylate (7:(1RS)-AECG ; such an abbreviation of a compound name is hereinafter described in a parenthesis and properly used) is synthesized, and then a fluoropropyl group is introduced thereinto at the N-8 position to synthesize methyl [1RS-(2-exo,3-exo)]-8-(3-fluoropropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (12:(1RS)-xcex2-CIT-FP). Specifically, 2,4,6-cycloheptatriene-1-carbonitrile (4:CHT-CN) is allowed to react with methylamine in methanol solvent in the presence of sodium hydroxide to obtain (1RS)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carbonitrile (6:(1RS)-AECG-CN). The cyano group of this compound is hydrolyzed and then converted to a methyl ester group to obtain methyl (1RS)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate (7:(1RS)-AECG), which is allowed to react with phenylmagnesium bromide (PhMgBr) by a well-known method to obtain methyl [1RS-(2-exo,3-exo)]-3-phenyl-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (8:(1RS)-xcex2-CPT). The tropane portion of this compound is converted to nortropane at the N-8 position, followed by substitution by a fluoropropane group at the N-8 position, whereby (1RS)-xcex2-CIT-FP 12 can be obtained. optically active (1R)-xcex2-CIT-FP can be obtained by optical resolution of (1RS)-xcex2-CIT-FP 12 or by subjecting (1RS)-nor-xcex2-CIT 11 to optical resolution to obtain an optically active substance in the course of the synthesis and continuing reactions shown in Reaction scheme C. 
According to the present inventive synthetic process using an anhydroecgonine derivative as an intermediate, it becomes possible to further shorten the procedure for synthesizing a phenyltropane derivative shown in the reaction scheme C. In detail, as the primary amine used in the first reaction step, i.e., the reaction of the cycloheptatriene derivative with the primary amine, there is properly chosen a primary amine having a substituent that the phenyltropane derivative is desired to have at the N-8 position, whereby the steps after the first reaction step, such as the introduction of the substituent can be omitted, so that the whole synthesis procedure can be shortened. An explanation is made below by giving a specific example. As shown in the reaction scheme D exhibited below, CHT-CN is allowed to react with fluoropropylamine at first to synthesize methyl [1RS-(2-exo,3-exo)]-8-(3-fluoropropyl)-8-azabicyclo[3.2.1]-oct-2-ene-2-carbonitrile (13:(1RS)-AECG-CN-FP) having a fluoropropyl group introduced thereinto at the N-8 position, which is converted to methyl [1RS-(2-exo,3-exo)]-8-(3-fluoropropyl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate (14:(1RS)-AECG-FP) and then methyl [1RS-(2-exo,3-exo)]-8-(3-fluoropropyl)-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate (15:(1RS)-xcex2-CPT-FP). Thus, the steps such as the conversion to a nortropane and the substitution by a fluoropropyl group are unnecessary after the synthesis of (1RS)-AECG-CN-FP, so that the whole procedure for synthesizing the final desired compound (1RS)-xcex2-CIT-FP can be shortened to 4 reaction steps from the 6 reaction steps of the procedure for synthesizing (1RS)-xcex2-CIT-FP shown in the reaction scheme C. 
In the reaction scheme D, the cyano group of (1RS)-AECG-CN-FP obtained by the reaction of CHT-CN with fluoropropylamine is converted to a methyl ester group before the Grignard reaction. On the other hand, the reaction scheme E exhibited below shows that the conversion to a methyl ester group can be carried out after the Grignard reaction. That is, the following is also possible: (1RS)-AECG-CN-FP is allowed to react with a Grignard reagent to obtain [1RS-(2-exo,3-exo)]-8-(3-fluoropropyl)-3-phenyl-8-azabicyclo[3.2.1]octane-2-carbonitrile (17:(1RS)-xcex2-CPT-CN-FP), and then (1RS)-xcex2-CIT-FP is obtained via (1RS)-xcex2-CPT-FP. A useful optically active substance such as (1R)-xcex2-CIT-FP can be obtained depending on purposes, by carrying out optical resolution in a proper stage in the reaction scheme. 
The optically active (1R)-xcex2-CIT-FP obtained in the manner described above is used as a radioactive imaging agent after being labeled with a radioisotope (Iodine-123 or Iodine-131) used as a substituent for the iodine atom of the 4-iodophenyl group. The labeling can be conducted by a well-known method such as a method in which a precursor for iodine labeling obtained by replacing the iodine atom with a trialkyltin group is allowed to react with sodium iodide of Iodine-123 or Iodine-131 in the presence of an oxidizing agent. The scheme C shows, as a specific example of the labeling, a case where xcex2-CIT-FP is converted to a trimethyltin compound 12-a, i.e., a precursor for iodine labeling, and then this compound is converted to a radioiodinated compound 12-b. Such a method for labeling by iododestannylation which gives a carrier free radioiodinated compound is widely adopted for synthesizing a radioactive-iodine-labeled compound of a substance capable of binding to receptors and is adopted for labeling a phenyltropane derivative obtained according to the present invention, with radioactive iodine.
When the phenyltropane compound is labeled with a radioisotope, a halogen atom (an iodine, bromine or fluorine atom) attached to the phenyl group at the 3-position of the phenyltropane compound may be replaced with a radioisotope as described above, or the substituent at the 2-position or N-8 position of the tropane ring may be labeled with a radioisotope. The following is also possible: the substituent at the 2-position or N-8 position of the tropane ring is replaced with a chelating group, and the chelating group is allowed to form a complex together with a radioactive transition metal nuclide useful for SPECT imaging, such as Technetium-99m, Rhenium-186, Rhenium-188 or the like to obtain a phenyltropane derivative labeled with the radioactive transition metal.
The chelating group for the radioactive transition metal includes diaminodithiols, monoamidomonoaminodithiols, diamidodithiols, triamidothiols, etc. Specific examples of the chelating group are diaminodithiols such as N,Nxe2x80x2-bis(2-mercaptoethyl)-ethylenediamine, 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol, etc.; monoamidomonoaminodithiols such as N-2-mercaptoethyl-2-mercaptoethylaminoacetamide, N-(2-mercaptoethyl)aminoethyl-2-mercaptoacetamide, etc.; diamidodithiols such as 1,2-ethylenebis(2-mercaptoacetamide), etc.; and triamidothiols such as mercaptoacetylglycylglycylglycine, etc.
The reaction scheme F exhibited below shows an example of procedure for synthesizing a phenyltropane derivative ([1RS-(2-exo,3-exo)]-2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-sulfanilethyl)amino]ethyl]amino]-ethanethiol trifluoroacetate 23) which has a diaminodithiol type chelating group introduced thereinto. That is, using CHT-CN as a starting material, methyl [1RS-(2-exo,3-exo)]-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (20:(1RS)-xcex2-CCIT) is synthesized via (1RS)-AECG-CN and (1RS)-AECG, and then there can be synthesized a phenyltropane derivative ([1RS-(2-exo,3-exo)]-2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-sulfanilethyl)-amino]ethyl]amino]ethanethiol trifluoroacetate 23) which has a diaminodithiol type chelating group as a substituent at the 2-position. 
The following reaction scheme G shows that the whole procedure for synthesizing a phenyltropane derivative capable of forming a chelate can be shortened by introducing a chelating group into the 2-position of the tropane skeleton of (1RS)-AECG-CN without esterifying the cyano group of (1RS)-AECG-CN. Thus, the procedure for synthesizing the final product, i.e., the phenyltropane derivative capable of forming a chelate can be shortened by using the anhydroecgonine derivative according to the present invention. 